This invention relates to therapeutic processes, and more particularly to a process for treating human postmenopausal symptoms.
Women in the postmenopausal age range now number approximately 40,000,000 in the United States alone, and each of these women faces an average life expectancy of 28 years beyond the last menstrual period. A recent review estimates that 75% to 85% of postmenopausal women will develop symptoms secondary to estrogen deficiency. C. Hammond, M.D., et al., "Current Status of Estrogen Therapy for the Menopause," Fertil. Steril, 37(1):5-25 (1982).
Perhaps the most common group of complaints of the patient following ovarian failure is the vasomotor symptom complex. The "hot flash" is classically described as a sudden onset of warmth in the face and neck which usually progresses to the chest. This sensation generally lasts several minutes and is often accompanied by a visible red flush. These episodes may be exceedingly uncomfortable and are frequently associated with dizziness, nausea, headaches, palpitations and diaphoresis. Estrogen supplementation will provide significant relief in over 90% of such patients.
Progressive atrophy of the genitourinary system commonly accompanies old age and is related both to estrogen deprivation and to the normal aging process. The vagina, cervix, corpus uteri, fallopian tubes, urethra and bladder trigone all have large numbers of estrogen receptors and are sensitive to a decrease in available estrogen. The vagina exhibits marked atrophic changes secondary to estrogen deprivation, characterized by thinning of the epithelium, loss of rugation and a reduction in lubrication during sexual intercourse. Atrophic vaginitis accounts for approximately 15% of postmenopausal bleeding and contributes significantly to dyspareunia.
Atrophy of the urethra in general parallels similar changes in the vagina. A significant consequence of urethral atrophy is the occurrence of dysuria, frequency of urination and urinary urgency. Systemic or intravaginal estrogen therapy dramatically reverses the atrophic process. The most serious of all postmenopausal complications is osteoporosis. In women over 60 years of age, 25% have documented spinal compression fractures as a result of osteoporosis. As many as 50% of women will have developed vertebral fractures by age 75. The risk of hip fractures increases with age and reaches 20% by age 90. Eighty percent (80%) of hip fractures are felt to be related to pre-existing osteoporosis. Even more devastating is the fact that approximately one-sixth of women with hip fractures die within three months following their fracture. A Mayo Clinic study calculates the health care costs of fracture hospital stays at over $1,000,000,000 per year. J. Gallagher, et al., "Epidemiology of Fractures of the Proximal Femur in Rochester, Minn., "Clin. Ortho. 150:163-171 (1980).
Numerous mechanisms for postmenopausal osteoporosis have been proposed, tested and reviewed. Current theories include contributions of dietary factors and calcium intake, aging, genetic susceptibility, Vitamin D status and the hormone control of bone deposition and absorption including roles for estrogen, androgens, parathyroid hormones, growth hormones and calcitonin. Current treatment for postmenopausal osteoporosis include fluoride, Vitamin D and calcium supplementation, increased physical activity and estrogen replacement therapy as the primary choice. The precise mechanism of the action of estrogen on bone metabolism is unknown. There are no estrogen receptors which have been identified in bone, and estrogen does not appear to stimulate osteoblastic activity. Estrogen therapy does not replace bone which has already been lost, and if discontinued, more rapid bone loss results.
Because of the potential severity and frequency of postmenopausal complications, long-term estrogen replacement therapy is a frequent practice. However, this has generated a great deal of controversy. Estrogen therapy has been implicated in the development of a variety of disorders. The Boston Collaborative Drug Surveillance Program indicated a summary risk ratio for gallbladder disease in postmenopausal women taking estrogen of 2.5. Boston Collab. Drug Surv., "Surgically Confirmed Gallbladder Disease, Venous Thromboembolism, and Breast Tumors in Relation to Postmenopausal Estrogen Therapy," N. Eng. J. Med. 290:15-19 (1974). Other studies have reported an association of estrogen replacement with hypertension, abnormal glucose tolerance, hypercoagulable states and arteriosclerosis, although these observations have not been confirmed, M. Crane, et al., "Hypertension, Oral Contraceptive Agents, and Conjugated Estrogens," Ann. Int. Med. 74(1):13-21 (1971); R. Pfeffer, "Estrogen Use, Hypertension and Stroke in Postmenopausal Women," J. Chron. Dis. 31:389-398 (1978); M. Notelovitz, "Metabolic Effect of Conjugated Oestrogens (USP) on Glucose Tolerance," So. African Med. J. 48(4):2599-2603 (1974); J. Stangel, et al., "The Effect of Conjugated Estrogens on Coagulability in Menopausal Women," Obstet. Gynecol. 49(3):314-316 (1977); T. Gordon, et al., "Menopause and Coronary Heart Disease," Ann. Int. Med. 89(2):157-161 (1978).
A role of estrogen in the development of benign breast disease has been suggested. The presence of estrogen receptors in the breast has been well documented, and estrogen may induce cystic or dysplastic changes demonstrated by mammography in postmenopausal women. Estrogen can induce mammary tumors in animals, particularly in susceptible strains of mice and rats. Some breast cancers in women respond to oophorectomy, suggesting a role in humans of estrogen in the stimulation and maintenance of breast neoplasia.
Unopposed estrogenic stimulation has also been implicated in the development of endometrial hyperplasia and endometrial carcinoma. Progestins given regularly and for a sufficient length of time appear to be protective against endometrial cancer. Postmenopausal women treated with estrogen-progestin combinations, however, frequently experience regular uterine bleeding which is unacceptable to many of them. For these reasons, an alternative to estrogen replacement therapy would have wide-spread application.
Efforts to counteract the ill effects of estrogen therapy include estrogen therapy coupled with short periods of antiestrogen supplementation. See A. Kauppila, et al., "Comparison of Megestrol Acetate and Clomiphene Citrate as Supplemental Medication in Postmenopausal Oestrogen Replacement Therapy," Arch. Gynecol. 234:49-58 (1983). In his study, Kauppila administered 1.25 mg/day conjugated oestrogens to postmenopausal women for 20 days. These 20 days were followed by a pause of 10 days. During every third pause, either 10 mg of megestrol acetate or 50 mg of clomiphene citrate, U.S. Pat. No. 2,914,563, was administered daily for 10 days. See also U.S. Pat. Nos. 4,061,733; 2,914,562; 2,914,564; and 3,634,517. Similar tests were reported by A. Kauppila, M.D., et al., "Postmenopausal Hormone Replacement Therapy With Estrogen Periodically Supplemented With Antiestrogen," Am. J. Obstet. Gynecol. 140(7):787-792 (1981). See also A. Wise, et al., "Quantitative Relationships of the Pituitary-Gonadal Axis in Postmenopausal Women," J. Lab. Clin. Med., 81(1):28- 36 (1973). These studies used estrogen as a part of the treatment.
The literature is replete with studies of the activity of antiestrogens in varying situations. See E. Su-Rong Huang and W. Miller, "Estrogenic and Antiestrogenic Effects of Enclomiphene and Zuclomiphene on Gonadotropin Secretion by Ovine Pituitary Cells in Culture," Endocrinology 112(2):442-448 (1983); A. Mukku, et al., "Stimulatory and Inhibitory Effects of Estrogen and Antiestrogen on Uterine Cell Division,"Endocrinology 109(4):1005-1010 (1981); M. Sankaran and M. Prasad, "A Critique on the Evaluation and Mode of Action of Antiestrogens", Hormones and Antagonists. Gynec. Invest. 3:143-147 (1972); L. Terenius and I. Ljungkvist, "Aspects on the Mode of Action of Antiestrogens and Antiprogestogens," Hormones and Antagonists. Gynec. Invest. 3:96-107 (1972); C. Geynet, et al., "Estrogens and Antiestrogens," Hormones and Antagonists. Gynec. Invest. 3:2-29 (1972); J. Wood, et al., "Estrogenic and Antiestrogenic Effects of Clomiphene, MER-25 and CN-55,945 -27 on the Rat Uterus and Vagina," Endocrinol. 82:69-74 (1968); K. Schulz et al., "Studies on Anti-Oestrogenic and Oestrogen-Like Action of Clomiphene Citrate--Animal Experiments," Hormones and Antagonists. Gynec. Invest. 3:135-141 (1972); J. Clark and B. Markaverich, "The Agonistic-Antagonistic Properties of Clomiphene: A Review," Pharmac. Ther. 15:467-519 (1982). See also, M. Pugeat, et al., "On Testing The Threshold of Sensitivity of the Gonadostate in the Late Menopausal Period: Effect of the Administration of Clomiphene Citrate or Ethynylestradiol on Plasma Levels of Gonadotropin, Testosterone and Delta-4 Androstendione," Eur. J. Obstet. Gynecol. Reprod. Biol. 9(3)-218-219 (1979); M. Zambrano, et al., "Evaluation of the Action of Clomiphene Citrate (Clomid) on Mouse Chromosomes by the Metaphase and Micronucleus Tests," Rev. Brasil. Genet. 2:339-344 (1982); J. Gennes, et al., "Clinical, Biological, Histological and Genetic Studies of De Morsier's Syndrome (Hypogonadotrophic Hypogonadism With Anosmia)", Ann. Endrocrinol. 31(5):841-861 (1970); I. Spita, et al., "The Decreased Basal and Stimulated Prolactin Levels in Isolated Gondotrophin [sic] Deficiency: A Consequence of the Low Oestrogen State," Clinical Endocrinology 16:423-432 (1982); S. Aksel, M.D., and G. Jones, M.D., "Etiology and Treatment of Dysfunctional Uterine Bleeding," J. Obstet. and Gynec. 44(1):1-13 (1974); T. Hashimoto, M.D., et al., "Endocrinological Study of Patients With Meningitis Tuberculosa," Jap. J. Med. 20(1):45-49 (1981); and, C. March, M.D., "Effect of Pretreatment with Clomiphene Citrate Upon Human Menopausal Gonadotropin Therapy for Anovulation, " Fertil. Steril. 26(2):191-192 (1975).
Many writers observed that some antiestrogens had weak estrogenic effects. Apparently due to concern about the compounded estrogenic effect which might arise when estrogen and weakly estrogenic antiestrogens are administered together, antigonadotropic agents which were substantially free from estrogenic effects began to appear, as shown in U.S. Pat. No. 3,843,727 and U.S. Pat. No. 3,697,581. These nonestrogenic antiestrogens were developed for administration along with estrogen to counteract the harmful effects of estrogen therapy.
Some researchers took an objective interest in the weak estrogenic effect of antiestrogens. See, T. Hashimoto, M.D., et al., "Dual Effect of Clomiphene Citrate on Pituitary Gonadotropin Secretion in Postmenopausal Women," Endocrinol. Jap. 23(2):115-118 (1976); T. Nencioni, et al., "Plasma FSH, LH and Prolactin Levels in Postmenopausal Women Undergoing Cyclofenil [sic] Treatment," Acta Obstet. Gynecol. Scand. 61:487-490 (1982); R. Young, et al., "Antiestrogen Effects on Gonadotropins and Uterus in the Ovariectomized Rat," Abstracts of the Endocrine Society #142, p. 108 (1979). But see, J. Clark, et al., "The Agonistic-Antagonistic Properties of Clomiphene: A Review," Pharmac. Ther. 15:467-519 (1982), in which the use of clomiphene is warned against; see also M. Pugeat, et al., "Effects of Clomiphene and Estrogens on Circulating Gonadotropins, Testosterone, Androstenedione, in Old Menopausal Women," Ann. Endocrinol. 38:363-365 (1977). One group studied the effects of the antiestrogen clomiphene in total body calcium in rats. A. LeBlanc, et al., " Effects of Clomiphen on Total Body Calcium in Aged Oophorectomized Rats," Calcium, Calcium Hormones, Abstract #7738, p. 1594 (1982).
In spite of all of the literature, there is currently no treatment for postmenopausal symptoms in which estrogen is not administered. A regime including estrogen may be workable for those women having only minor contraindications to estrogen therapy; however, for some women, estrogen is absolutely contraindicated. For these women, there is presently no satisfactory treatment.